First symptoms use to manifest in early infancy. The absence of mature osteoclasts interferes with skeletal growth, including, but not limited to, the development of the skull. Children may be macrocephalic [1]. In any case, anomalies of skull growth adversely affect the development of the central nervous system, and infants are likely to present signs and symptoms of mental and motor retardation [2]. Furthermore, excessive bone tends to obturate cranial nerve foramina and provoke cranial nerve palsy. The optic foramina are most commonly affected, and the majority of OPTB7 patients presents with progressive visual impairment due to optic nerve compression. Vision loss results in blindness, and blindness may even be congenital [1]. Nystagmus is another common finding.

Medullary cavities are likewise filled up with bone tissue, inducing a shift of hematopoiesis from the marrow to the liver and spleen. Hepatosplenomegaly is the clinical equivalent of this process and may entail gastroesophageal reflux [1], but the patients' body is not usually able to compensate for the loss of bone marrow spaces. Cytopenias may ensue. Those suffering from anemia may present with pallor and chronic fatigue, while thrombocytopenia gives rise to a hemorrhagic diathesis. Leukopenia may account for increased susceptibility to infection and is observed in several types of autosomal recessive osteopetrosis. In OPTB7, however, immunodeficiency is aggravated by a second mechanism inherent to B-cell function: The patients' antibody response is largely impaired, and laboratory analyses of blood samples may reveal severe hypogammaglobulinemia, even in the presence of normal lymphocyte counts. Accordingly, affected children may have recurrent infections, often severe, sometimes life-threatening. Pneumonia is a dreaded complication of OPTB7, and respiratory disorders have repeatedly been named as a cause of death [1] [2]. It shall be mentioned, though, that the immunological features of OPTB7 are variable and may possibly change over the course of the disease [1].

The underlying disorder of bone remodeling may entail electrolyte imbalances and thus a variety of additional symptoms. In this context, several patients have been reported to suffer from hypotonia and seizures, cardiac and respiratory arrest.

• Splenomegaly

  Some with hepatomegaly, splenomegaly or hepatosplenomegaly. [autoinflammatory-search.org]

  A 5-month-old boy developed splenomegaly, anemia, thrombocytopenia with elevated white cells, monocytosis and immature granulocytes in the peripheral blood. Bone marrow showed dysplasia without blastosis. [pubfacts.com]

  Affiliated tissues include bone, bone marrow and eye, and related phenotypes are facial palsy and splenomegaly Disease Ontology : 12 An osteopetrosis characterized by autosomal recessive inheritance that has material basis in homozygous or compound heterozygous [malacards.org]

  After this, he developed symptoms such as low platelet, low hemoglobin, splenomegaly and hydrocephalus. The patient was started with fortnightly blood transfusions. [molecularcytogenetics.biomedcentral.com]

  He had no splenomegaly and his laboratory findings were within normal limits. In 1993 he sustained a subtrochanteric fracture of his right hip that was treated with dynamic hip screw fixation. [healio.com]

• Anemia

  AR 191 677 FANCB Fanconi anemia XL 11 21 FANCC Fanconi anemia AR 94 64 FANCD2 * Fanconi anemia AR 21 61 FANCE Fanconi anemia AR 4 17 FANCF Fanconia anemia AR 7 16 FANCG Fanconi anemia AR 16 92 FANCI Fanconi anemia AR 13 45 FANCL Fanconi anemia AR 13 [blueprintgenetics.com]

  As a result, people with severe osteopetrosis are at risk of abnormal bleeding, a shortage of red blood cells (anemia), and recurrent infections. [ncbi.nlm.nih.gov]

  Among these, those that have been treated with cord blood are Fanconi’s Anemia, Severe Aplastic Anemia, Pure Red Cell Aplasia, Paroxysmal Nocturnal Hemoglobinuria (PNH), and Congenital Dyserythropoietic Anemia. [babyinfo.com.au]

  Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. [uniprot.org]

  Patients typically present infantile malignant osteopetrosis (manifesting with increased bone density, bone fractures, abnormal eye movements/visual loss, nystagmus), hematologic abnormalities with bone marrow failure (e.g. anemia, hepatosplenomegaly) [orpha.net]

• Short Stature

  Depending on severity and age of onset, features may includefractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures ,and life-threatening pancytopenia. [monarchinitiative.org]

  Depending on severity and age of onset, features may include fractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia. [malacards.org]

• Developmental Delay

  Previously existing developmental delays and visual impairment, however, could not be reversed. [symptoma.com]

  delay Hydrocephalus Hypocalcemic seizures Motor delay Optic nerve compression Abnormality of the respiratory system Recurrent pneumonia Growth abnormality Growth delay IMPORTANT NOTE: NIH does not independently verify information submitted to the GTR [ncbi.nlm.nih.gov]

  Most common symptoms of PAGET DISEASE OF BONE 5, JUVENILE-ONSET; PDB5 Autosomal recessive inheritance Global developmental delay Short stature Hearing impairment Sensorineural hearing impairment More info about PAGET DISEASE OF BONE 5, JUVENILE-ONSET; [mendelian.co]

  delay 0001263 Growth delay Delayed growth Growth deficiency Growth failure Growth retardation Poor growth Retarded growth [ more ] 0001510 Hepatomegaly Enlarged liver 0002240 Hydrocephalus Too much cerebrospinal fluid in the brain 0000238 Hypocalcemic [rarediseases.info.nih.gov]

• Fever

  Dermographism. [13] Intermittent fevers can rise >40°C. Chills are uncommon. Fatigue and headaches are common with fevers. [autoinflammatory-search.org]

  Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. [nectarmutation.org]

  […] diaphyses / long bones - Craniostenosis / craniosynostosis / sutural synostosis - Delayed dentition / eruption of teeth / lack of eruption of teeth - Ecchymoses - Epiphyseal anomaly - Failure to thrive / difficulties for feeding in infancy / growth delay - Fever [csbg.cnb.csic.es]

  Rheumatic fever : Rheumatic fever is categorized as a rare disease. A Fever means a... RHS Type II : See Ramsay Hunt Syndrome Type 2. RTS : See Rubinstein-Taybi Syndrome. Russell-Silver syndrome : See Silver-Russell Dwarfism. [psychforums.com]

  Dermatomyositis Diffuse astrocytoma Duplication/inversion 15q11 Dysosteosclerosis Enthesitis-related juvenile idiopathic arthritis Ependymoblastoma Epilepsy syndrome Epilepsy-telangiectasia syndrome Ewing sarcoma Fabry disease Familial Mediterranean fever [se-atlas.de]

• Tall Stature

  Marfan syndrome (MIM 154700) is a connective tissue disorder characterized by abnormalities of the skeleton (tall stature, long limbs, arachnodactyly, joint laxity, osteopenia, scoliosis/lordosis, highly arched palate, dental crowding), eye (myopia, lenticular [content.iospress.com]

• Respiratory Distress

  The procedure itself is related to significant morbidity and mortality, with hypercalcemia, nephrocalcinosis, respiratory distress, and fractures being most frequently observed during follow-ups. [symptoma.com]

  Non-infectious conjunctivitis may be caused by DIRA. [15] [16] Some with respiratory distress. One known case of pulmonary hemosiderosis with progressive interstitial fibrosis. [15] [16] [17] DIRA patients rarely have gastrointestinal issues. [autoinflammatory-search.org]

• Vomiting

  Life-threatening disease characterized by episodic vomiting, lethargy and ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia, developmental retardation, and intolerance to protein. [ read more ] 10101253 12559849 15059621 10329019 [nectarmutation.org]

  Vomiting and diarrhea during flares. Splenomegaly, transaminitis. Inflammatory infiltrates are noted in the intestine. [autoinflammatory-search.org]

  Creutzfeldt-Jakob Disease Cri-Du-Chat Syndrome Crohn’s Disease Crouzon Syndrome Cryoglobulinemia Cryopin Associated Periodic Syndromes (CAPS) Cullin-4B Mutation Cushing Syndrome Cutis laxa Chlq2-1 micro del Cutis marmorata telangiectatica congenita (CMTC) Cyclic Vomiting [geneticalliance.org.au]

• Gagging

  A single nucleotide change is present in exon 11 (c1305 G > T), which causes an amino acid substitution: Glu (GAG) to Asp (GAT). [jstage.jst.go.jp]

• Nausea

  Risk for cardiac arrest and septicemia. [58] [61] Nausea during flares. [autoinflammatory-search.org]

• Hepatosplenomegaly

  Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. [nectarmutation.org]

  Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. [uniprot.org]

  Patients typically present infantile malignant osteopetrosis (manifesting with increased bone density, bone fractures, abnormal eye movements/visual loss, nystagmus), hematologic abnormalities with bone marrow failure (e.g. anemia, hepatosplenomegaly) [orpha.net]

  Extramedullary hematopoiesis leads to hepatosplenomegaly. [1] The extramedullary hematopoiesis leading to hepatosplenomegaly was noted in the index patient. [wajradiology.org]

• Hepatomegaly

  Some with hepatomegaly, splenomegaly or hepatosplenomegaly. [autoinflammatory-search.org]

  ODFR, OFE, OPTB7, OSTS, PDB2, RANK, TRANCE-R, TRANCER, TNFRSF11A Summary: TNF receptor superfamily member 11a Show allHide all Abnormality of blood and blood-forming tissues Anemia Abnormality of limbs Femur fracture Abnormality of the digestive system Hepatomegaly [ncbi.nlm.nih.gov]

  […] sutural synostosis - Delayed dentition / eruption of teeth / lack of eruption of teeth - Ecchymoses - Epiphyseal anomaly - Failure to thrive / difficulties for feeding in infancy / growth delay - Fever / chilling - Hearing loss / hypoacusia / deafness - Hepatomegaly [csbg.cnb.csic.es]

  […] fracture 0031846 Generalized hypotonia Decreased muscle tone Low muscle tone [ more ] 0001290 Global developmental delay 0001263 Growth delay Delayed growth Growth deficiency Growth failure Growth retardation Poor growth Retarded growth [ more ] 0001510 Hepatomegaly [rarediseases.info.nih.gov]

• Hypertension

  These findings indicated that the patient suffered from pulmonary hypertension. Despite intensive care, the patient died of cardiac failure at the age of 16 months. [jstage.jst.go.jp]

  Occasional - Apnea / sleep apnea - Cranial nerves palsy - Hemorrhage / hemorrhagic syndrome / excessive / long-lasting bleeding - Hypocalcemia - Hypophosphatemia - Pulmonary artery stenosis / absence / hypoplasia of the pulmonary branches - Pulmonary hypertension [csbg.cnb.csic.es]

  View Article : Google Scholar : PubMed/NCBI 9 Kuroyanagi Y, Kawasaki H, Noda Y, Ohmachi T, Sekiya S, Yoshimura K, Ohe C, Michigami T, Ozono K and Kaneko K: A fatal case of infantile malignant osteopetrosis complicated by pulmonary arterial hypertension [spandidos-publications.com]

  Hypothyroidism I Idiopathic Pulmonary Fibrosis Idiopathic Spastic Paraparesis Idiopathic Thrombocytopenic Purpura (immune thrombocytopenia) Immunodeficiency Incontinentia Pigmenti Infantile Neuroaxonal Dystrophy (INAD) Intestinal Failure Intracranial Hypertension [geneticalliance.org.au]

  A fatal case of infantile malignant osteopetrosis complicated by pulmonary arterial hypertension after hematopoietic stem cell transplantation. Tohoku J Exp Med 2014 ; 234: 309 – 312. Google Scholar | Crossref | Medline 6. [journals.sagepub.com]

• Heart Disease

  The book provides you with all the at-a-glance information you need for a quick overview of common issues from nutrition, allergy, infectious disease, and adolescent medicine, to cancer and heart disease. [books.google.com]

  Etiology Mobitz type I (Wenckebach) is often a normal variant and seen in individuals with a high vagal tone without evidence of structural heart disease. [ncbi.nlm.nih.gov]

  (HBD) Hypophosphatemic Rickets Hypopituitarism Hypoplastic Left Heart Syndrome Hypoplastic Left Heart Syndrome Hypotension Orthostatic Hypothyroidism I Idiopathic Pulmonary Fibrosis Idiopathic Spastic Paraparesis Idiopathic Thrombocytopenic Purpura [geneticalliance.org.au]

  WBS is characterized by a distinctive pixie-like face (flat nasal bridge, upturned nose, full lips), congenital heart disease (supravalvular aortic stenosis, peripheral pulmonary arterial stenoses, mitral valve prolapse), developmental delay (mean IQ [content.iospress.com]

• Heart Failure

  Failure Society of America, Cardiac Electrophysiology Society, American College of Physicians, American Heart Association, American Medical Association, Illinois State Medical Society Disclosure: Nothing to disclose. [medscape.com]

  At risk for being underweight, or failure to thrive. At risk for multi-organ failure and death. [26], [27] Large abdomen from an enlarged liver and spleen is possible. [autoinflammatory-search.org]

• Blister

  Some with intestinal symptoms. [68] Erythematous plaques and vesiculopustular blistering rash that intensifies with heat & sun exposure. [autoinflammatory-search.org]

• Osteoporosis

  Unit, Department of Osteoporosis and Bone Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. a Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Disease, Shanghai Jiao Tong [wwww.unboundmedicine.com]

  (PMID: 17115234) Koh JM … Shin HD (Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2007) 3 22 45 60 [genecards.org]

  […] of usually difficult to find information on the investigation of pediatric bone disease and reference values Covers both the physiology of bone and mineral homeostasis in children and diseases in one book Inhalt Chapter 18 The Spectrum of Pediatric Osteoporosis [books.google.de]

  Metabolic anomalies - Metaphyseal anomaly - Movement disorder - Mutiple fractures / bone fragility - Narrow rib cage / thorax - Nasal congestion / sinusitis / rhinitis / rhinorrhea - Nystagmus - Optic nerve anomaly / optic atrophy / anomaly of the papilla - Osteoporosis [csbg.cnb.csic.es]

  In sum, the absence of multinucleated and active osteoclasts in excessively dense osseous tissue allows for the diagnosis of an osteoclast-poor form of osteoporosis. [symptoma.com]

• Muscular Atrophy

  atrophy, Progressive bulbar palsy, Pseudobulbar palsy, Primary lateral sclerosis, Motor neurone disease Anderson-Fabry disease Androgen insensitivity syndrome AIS, Androgen resistance syndrome, Testicular feminisation syndrome Androgen resistance syndrome [socialstyrelsen.se]

  Juvenile Retinoschisis : See Juvenile X-Linked Retinoschisis. juvenile rheumatoid arthritis : See Systemic Onset Juvenile Rheumatoid Arthritis. juvenile spinal muscular atrophy : See Spinal Muscular Atrophy. [psychforums.com]

  (Kjer's Atrophy) Dorsal pancreatic agenesis Double Y Syndrome Down Syndrome (Trisomy 21) Dravet Syndrome Duane Syndrome Dubowitz Syndrome Duchenne Muscular Dystrophy Duncan Syndrome Dupuytren's Contracture Dysautonomia Dyschondrosteosis Dyskeratosis [geneticalliance.org.au]

• Back Pain

  Affiliated tissues include bone, bone marrow and eye, and related phenotypes are generalized osteosclerosis and back pain Disease Ontology : 12 An osteopetrosis characterized by autosomal recessive inheritance of that has material basis in mutation in [malacards.org]

  Other symptoms include bone pain, recurrent fractures, back pain, and degenerative arthritis [13]. [hindawi.com]

  As would be expected, many of the affected subjects with severe fractures also reported long-term pain and disability. [academic.oup.com]

• Myalgia

  BORNHOLM DISEASE / DEFINITION bornholm disease otherwise known as the devil's grip, the epidemic myalgia, or the epidemic pleurodynia, the epidemic transient diaphragmatic spasm or the grasp of the phantom is a medical condition that is brought about [signssymptoms.org]

  Fevers 39–40°C myalgia, headaches with flares. Sensorineural hearing loss. [autoinflammatory-search.org]

• Arthralgia

  Ankle arthralgias are common. [autoinflammatory-search.org]

• Progressive Visual Loss

  visual loss Progressive loss of vision Progressive vision loss Progressive visual impairment Slowly progressive visual loss Vision loss, progressive Visual loss, progressive [ more ] 0000529 Proptosis Bulging eye Eyeballs bulging out Prominent eyes Prominent [rarediseases.info.nih.gov]

• Progressive Loss of Vision

  […] visual loss Progressive loss of vision Progressive vision loss Progressive visual impairment Slowly progressive visual loss Vision loss, progressive Visual loss, progressive [ more ] 0000529 Proptosis Bulging eye Eyeballs bulging out Prominent eyes Prominent [rarediseases.info.nih.gov]

• Lacrimation

  Inflamed conjunctiva (conjunctivitis), and/or inflammation of the lacrimal glands, retina and optic nerves is common. [34] Some have atrial hypertension and/or pericarditis. [autoinflammatory-search.org]

• Hematuria

  A novel FN1 variant associated with familial hematuria: TBMN? Clin Biochem. 2016. DOI: 10.1016/j.clinbiochem.2016.01.026. Google Scholar 20. Aggarwal, S. [journals.sagepub.com]

  Hematuria, proteinuria, glomerulonephritis. [97] Splenomegaly. Some with lymphadenopathy. [97] Arthralgia, arthritis. Some with relapsing polychondritis. [autoinflammatory-search.org]

• Seizure

  In addition, some affected individuals may have seizures due to low blood calcium levels. Intellectual disability (usually mild to moderate) may result from recurrent seizures and/or brain abnormalities that may occur in some individuals with ARO1. [myriadwomenshealth.com]

  Depending on severity and age of onset, features may includefractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures ,and life-threatening pancytopenia. [monarchinitiative.org]

  Depending on severity and age of onset, features may include fractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia. [rarediseases.info.nih.gov]

• Nystagmus

  Patients typically present infantile malignant osteopetrosis (manifesting with increased bone density, bone fractures, abnormal eye movements/visual loss, nystagmus), hematologic abnormalities with bone marrow failure (e.g. anemia, hepatosplenomegaly) [orpha.net]

  Affiliated tissues include bone and bone marrow, and related phenotypes are decreased antibody level in blood and nystagmus Disease Ontology : 12 An osteopetrosis characterized by autosomal recessive inheritance that has material basis in homozygous or [malacards.org]

  TRANCE-R, TRANCER, TNFRSF11A Summary: TNF receptor superfamily member 11a Show allHide all Abnormality of blood and blood-forming tissues Anemia Abnormality of limbs Femur fracture Abnormality of the digestive system Hepatomegaly Abnormality of the eye Nystagmus [ncbi.nlm.nih.gov]

  […] polyadenopathies - Macrocephaly / macrocrania / megalocephaly / megacephaly - Metabolic anomalies - Metaphyseal anomaly - Movement disorder - Mutiple fractures / bone fragility - Narrow rib cage / thorax - Nasal congestion / sinusitis / rhinitis / rhinorrhea - Nystagmus [csbg.cnb.csic.es]

• Ataxia

  Granulomatous Disease X-Linked Agammaglobulinemia Hypogammaglobulinemia Selective IgA Deficiency Wiskott-Aldrich Syndrome IgG Subclass Deficiency Hyper IgM Syndrome Specific Antibody Deficiency DiGeorge Syndrome Hyper IgE Syndrome NEMO Deficiency Syndrome Ataxia-Telangiectasia [dev.primaryimmune.org]

  Ataxia-Telangiectasia ATR16 Syndrome Atypical Haemolytic Uraemic Syndrome (aHUS) Autism Spectrum Autoimmune Inflammatory Arthropathy Autoimmune kidney disease Autoimmune Lymphoproliferative Syndrome (ALPS) Autoinflammatory Diseases Autosomal dominant [geneticalliance.org.au]

  […] corporis diffusum Angioosteohypertrophy syndrome Anhidrotic ectodermal dysplasia Aniridia Apert syndrome Acrocephalosyndactyly type 1 Argininosuccinate lyase deficiency ASL deficiency Arteriohepatic dysplasia ASL deficiency Aspartylglucosaminuria AGU AT Ataxia [socialstyrelsen.se]

  NCT02422108 Phase 2 Denosumab 8 Denosumab (A Monoclonal Antibody to Receptor Activator of Nuclear Factor-Kappa B Ligand (RANKL) in Crohn's Disease Completed NCT02321280 Phase 1, Phase 2 Denosumab 9 Safety and Efficacy of γIFN Treatment in Friedreich Ataxia [malacards.org]

  […] epilepsy syndrome Albers-Schönberg osteopetrosis Alport syndrome Anaplastic astrocytoma Angelman syndrome Anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome Aplastic anemia Aromatase excess syndrome Astroblastoma Astrocytoma Ataxia-telangiectasia [se-atlas.de]

• Stroke

  […] damage. there are strokes that damage part of one's brain & some have permanent injury. tia is important in foreseeing if a "stroke" will happen & the chance to prevent it. they may occur several days, some weeks, or even a few months prior to a major [signssymptoms.org]

  Stroke, 1997, 282222-2229. 2 Razvi SS, Bone I. Single gene disorders causing ischemic stroke [J]. J Neurol, 2006, 253685-700.3 Van Den Boom R, Lesnik Oberstein SA, Van Duinen SG, et al. [zhwenku.com]

  Some patients do not have strokes. [131] Possible adult stroke risk. [autoinflammatory-search.org]

  Stroke 1986;17:106-110 Wilms G, Casaer P, Alliet P, et al. Cerebrovascular occlusive complications in osteopetrosis major. Neuroradiology 1990;32:511-513 ↵ Curé JK, Key LL, Shankar L, Gross AJ. [ajnr.org]

• Cerebellar Ataxia

  ARCA1 : See Autosomal Recessive Cerebellar Ataxia. Arthrogryposis Multiplex Congenita : Arthrogryposis Multiplex Congenita is categori... All the definitions starting by the letter A. [psychforums.com]

  Ataxia Atrophy Cerebellar Atrophy Cerebellar Hypoplasia Cerebrocostomandibular syndrome Cerebrotendinous xanthomatosis Ceroide Neuronal Phase 1 Charcot-Marie-Tooth Disease Charcot-Marie-Tooth Type II CHARGE Syndrome Choanal Atresia Chondrodysplasia Chorioretinal [geneticalliance.org.au]

The diagnosis of osteopetrosis is based on diagnostic imaging [3]. Increased bone density can be recognized within the first months of life, and alternating lucent bands may be seen in the metaphyses of appendicular bones. Moreover, multiple fractures may be observed. Neuroimaging may reveal the causes of cranial nerve palsies and vision loss, namely the atrophy of the respective nerves due to bone compression. Additional anomalies may or may not be present; ventricular enlargement and Chiari malformation type 1 have been reported [1] [2].

The histological examination of bone and bone marrow biopsy specimens reveals the retention of large areas of cartilage, thickened trabecular bone with reduced resorption lacunae and very few osteoclasts, as well as narrowing of medullary cavities [3]. There may be abundant stem cells in the scarce marrow spaces, but reduced cellularity has also been described. In sum, the absence of multinucleated and active osteoclasts in excessively dense osseous tissue allows for the diagnosis of an osteoclast-poor form of osteoporosis [2].

There are two types of osteoclast-poor osteopetrosis, both of which involve abnormalities in the same signaling pathway: autosomal recessive osteopetrosis 2 and OPTB7 [1]. The diagnosis of OPTB7 thus has to be confirmed by means of genetic studies [3].

Hematopoietic stem cell transplantation has been carried out in several OPTB7 patients and continues to be the recommended approach to therapy. In order to avoid irreversible sequelae, it should be realized as soon as possible. Guerrini and colleagues described a total of four children who underwent the procedure, two of which succumbed to complications, while the other two remained alive years after receiving their transplants [2]. The same team of scientists treated five more patients in the following years and could prevent mortality in this group. These patients were transplanted at different ages, the oldest child being 12 years old when undergoing the procedure, and were reported to be alive and reasonably well until the end of the study, at a maximum of 3 years after the transplantation. Previously existing developmental delays and visual impairment, however, could not be reversed [1].

OPTB7 patients are irresponsive to the administration of RANKL, since the differentiation of osteoclasts is interrupted downstream of the release of this cytokine. Even if available in excess, signals cannot be transmitted into the cell. Drugs aiming at rectifying the cause of growth failure would need to target elements situated even further downstream in the signaling cascade, but no such compounds have yet been used to manage OPTB7.

Hematopoietic stem cell transplantation has been shown to resolve the radiological features of osteopetrosis [1] [2]. Unfortunately, though, damage to nervous structures is largely irreversible. Patients are unlikely to compensate for developmental delays and improvements in vision are not to be expected [2]. Similarly, stem cell transplantations will not necessarily reverse skeletal deformities and induce compensatory growth [4]. The procedure itself is related to significant morbidity and mortality, with hypercalcemia, nephrocalcinosis, respiratory distress, and fractures being most frequently observed during follow-ups. The former may be related to the compensatory overexpression of RANKL [1].

Little is known about the long-term prognosis of OPTB7 patients who do not receive stem cell transplants. Individual patients have been described to live for years without presenting recurrent infections, while others died in infancy or childhood [2]. These observations support the hypothesis of phenotypic variability in OPTB7 [1].

OPTB7 is caused by mutations in the TNFRSF11A gene. TNFRSF11A is located on the long arm of chromosome 18 and encodes for member 11A of the superfamily of tumor necrosis factor receptors. This receptor is involved in the development of osteoclasts and lymph nodes, and has been shown to regulate the interaction between T cells and dendritic cells. Nonsense mutations, missense mutations, and the insertion of a single nucleotide into the TNFRSF11A gene have been described in OPTB7 patients, who may be homozygous or compound heterozygous for pathogenic variants of the gene. To date, a total of twelve TNFRSF11A mutations have been linked to OPTB7, and they have been identified in eleven families [1] [2].

Autosomal recessive osteopetrosis is a rare disease, the incidence of which has been estimated at 1 in 250,000 live births [5]. OPTB7, however, accounts for a very small share of these cases, with only about a dozen cases described in the literature. In detail, eleven families have been described to harbor pathogenic variants of the TNFSF11A gene, and these families originate from distinct parts of the world. Parental consanguinity has been noted in the majority of cases, but few mutations have been found in more than one family, so epidemiological data argue against a role of founder effects as they have been described for other types of autosomal recessive osteopetrosis [1] [2].

TNFRSF11A mutations have also been related to familial expansile osteolysis, expansile skeletal hyperphosphatasia, Paget disease of bone type 2, and dysosteosclerosis [6] [7]. There are significant differences between those diseases and OPTB7: While accelerated bone turnover, focal bone involvement, and dominant inheritance are attributed to the former, dysosteosclerosis and OPTB7 are generalized, sclerosing bone diseases inherited in an autosomal recessive manner [5]. The common denominator of these conditions is an imbalance between the formation and resorption of bone tissue, a disorder of RANKL-mediated osteoclastogenesis.

RANKL is short for RANK ligand, where RANK is another name for TNFRSF11A. RANKL is the main osteoclast differentiation factor and is expressed by osteoblasts and stromal stem cells, while RANK is to be found on the surface of osteoclasts and their precursors [1]. Binding of RANKL to RANK activates the RANK/RANKL/osteoprotegerin signaling pathway, promotes the differentiation of osteoclast precursors into multinucleated, active osteoclasts, and thus favors bone resorption over bone formation. In patients suffering from osteolytic disorders, TNFRSF11A mutations lead to increased constitutive RANK signaling. OPTB7 and dysosteosclerosis, by contrast, are related to loss-of-function mutations and a significant decrease of RANK-mediated actions [7].

Besides osteoclast differentiation, the RANK receptor is implied in signaling pathways within the immune system. When TNFRSF11A mutations were first linked to the disease, it has been hypothesized that OPTB7 patients suffer from a partial failure in peripheral B cell maturation. RANK was speculated to be involved in the process of Ig switch and antibody maturation, or in the formation of secondary lymphoid tissues [2].

Genetic counseling should be provided to affected families, but these are not usually identified until a child is diagnosed with OPTB7. Therefore, the consequent workup of suspect cases forms the basis of disease prevention. The identification of the underlying mutation(s) allows for prenatal diagnosis to be made in the course of the next pregnancy and opens up the possibility to reach an informed decision. Ideas on future therapies of OPTB7 also include the transplantation of hematopoietic stem cells in utero, and this procedure would have to rest on prenatal diagnosis [4] [8]. Beyond that, education about the risks of consanguineous marriage may prevent such circumstances from occurring.

Autosomal recessive osteopetrosis is a general term referring to a group of disorders associated with impaired bone resorption. Initially, all types of autosomal recessive osteopetrosis were assumed to be related to increased numbers of dysfunctional osteoclasts [4]. In recent years, however, several case reports were published that include somewhat surprising results of bone biopsies: There were virtually no osteoclasts in these patients' bone tissue, and these findings have been explained by a disorder of osteoclastogenesis.

The identification of distinct gene defects and their respective impact on osteoclast differentiation, maturation, and function has given rise to the current classification of autosomal recessive osteopetrosis [4] [9]. There are at least eight types of the disease, two of which are characterized by the absence of osteoclasts [1]. Extensions of the existing scheme are to be expected in the near future, when additional mutations are determined that may give rise to osteopetrosis: For about one-third of all cases of osteoclast-poor osteopetrosis, the etiology remains unknown [2].

OPTB7 has been linked to mutations in the TNFRSF11A gene in 2008, by an Italian team of scientists. Guerrini et al. associated OPTB7 with impaired RANK/RANKL signaling, which plays a key role in osteoclast differentiation and lymphocyte function [2].

Autosomal recessive osteopetrosis 7 (OPTB7) is a very rare disease, with only about a dozen cases being described until today. OPTB7 is a hereditary disorder caused by mutations in the TNFRSF11A gene. This gene encodes for a protein that is involved in the differentiation of osteoclasts and the production of antibodies by B cells:

• Growth requires a continuous adaptation of bone structures, a tight balance of the formation and resorption of osseous tissue. The main function of osteoclasts is the resorption of bone tissue, so any lack of osteoclasts induces an increase in bone density. This condition is called osteopetrosis.
• B cells are specialized lymphocytes. They should be able to produce antibodies to combat infections, but this process is impaired in OPTB7 patients. Those who are unable to produce antibodies are diagnosed with hypogammaglobulinemia.

Accordingly, those suffering from OPTB7 present with excessively dense, fragile bones and susceptibility to severe, sometimes life-threatening infections. Impaired bone remodeling also interferes with the development and function of the nervous system, giving rise to mental retardation, visual impairment, and possibly other neurological deficits.

The diagnosis of OPTB7 is based on diagnostic imaging, laboratory analyses, and genetic studies. While the former provide important clues as to the cause of the disease, each case should be confirmed by means of the identification of the underlying mutation. What's more, precise knowledge regarding the mutation of TNFRSF11A allows for genetic counseling and prenatal diagnosis to be made in a possible future pregnancy.

OPTB7 have successfully been treated with hematopoietic stem cell transplantation. This procedure, however, is related to significant morbidity and mortality and does not affect existing damage to the nervous system. Ideally, OPTB7 should be prevented. In this context, it should be beared in mind that consanguineous marriage is a major risk factor for OPTB7 and many other hereditary disorders, and, if this practice was abolished, most cases of OPTB7 could be avoided.

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